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Nonalcoholic fatty liver disease in CLOCK mutant mice
Xiaoyue Pan, … , Joyce Queiroz, M. Mahmood Hussain
Xiaoyue Pan, … , Joyce Queiroz, M. Mahmood Hussain
Published May 12, 2020
Citation Information: J Clin Invest. 2020;130(8):4282-4300. https://doi.org/10.1172/JCI132765.
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Research Article Hepatology Metabolism

Nonalcoholic fatty liver disease in CLOCK mutant mice

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is becoming a major health issue as obesity increases around the world. We studied the effect of a circadian locomotor output cycles kaput (CLOCK) mutant (ClkΔ19/Δ19) protein on hepatic lipid metabolism in C57BL/6 Clkwt/wt and apolipoprotein E–deficient (Apoe−/−) mice. Both ClkΔ19/Δ19 and ClkΔ19/Δ19 Apoe−/− mice developed a full spectrum of liver diseases (steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma) recognized in human NAFLD when challenged with a Western diet, lipopolysaccharide, or CoCl2. We identified induction of CD36 and hypoxia-inducible factor 1α (HIF1α) proteins as contributing factors for NAFLD. Mechanistic studies showed that WT CLOCK protein interacted with the E-box enhancer elements in the promoters of the proline hydroxylase domain (PHD) proteins to increase expression. In ClkΔ19/Δ19 mice, PHD levels were low, and HIF1α protein levels were increased. When its levels were high, HIF1α interacted with the Cd36 promoter to augment expression and enhance fatty acid uptake. Thus, these studies establish a regulatory link among circadian rhythms, hypoxia response, fatty acid uptake, and NAFLD. The mouse models described here may be useful for further mechanistic studies in the progression of liver diseases and in the discovery of drugs for the treatment of these disorders.

Authors

Xiaoyue Pan, Joyce Queiroz, M. Mahmood Hussain

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Figure 4

LPS-induced hepatosteatosis and cirrhosis in ClkΔ19/Δ19 mice.

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LPS-induced hepatosteatosis and cirrhosis in ClkΔ19/Δ19 mice.
Male (8-mo...
Male (8-month-old) ClkΔ19/Δ19 and Clkwt/wt mice on a chow diet were fed a Western diet for 2 months and injected i.p. with LPS (0.25 mg/kg per injection, 3 times on alternate days). Mice then continued on a Western diet for an additional 2 months, and livers and plasma were collected for analyses at the end (n = 6 per group). (A) Livers from LPS-injected ClkΔ19/Δ19 mice showed hepatomegaly and micronodular cirrhosis. Pictures are representative of 2 experiments. (B) Frozen liver sections were stained with Oil Red O, H&E, and anti-macrophage antibodies. Representative of 2 experiments. (C and D) Liver pieces were used to measure triglyceride, cholesterol (C), and TBARS (D) levels. Mean ± SD; **P < 0.01, ***P < 0.0001, Welch’s 2-tailed t test. (E) Plasma ALT and β-HB levels were measured in LPS-injected ClkΔ19/Δ19 mice. Mean ± SD; *P < 0.05, ***P < 0.0001, Welch’s 2-tailed t test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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